The objective of this Core is to better characterize the mechanisms and neuromedical outcomes of the neuropsychological (NP) impairment frequently seen in patients infected with HIV-1. By following a large cohort of HIV seropositive individuals to death and relating their NP deficits to neuropathological, virological, immunological and neuroimaging findings, we expect to advance our understanding of the processes underlying HIV- related NP impairment. In so doing, we should help determine why some patients do and others do not develop this common and often debilitating consequence of HIV infection. Ultimately, such information may aid in establishing bases for treatment. During the initial HNRC funding period the scientific emphasis was on the early and often subtle HIV-associated NP changes, primarily in medically asymptomatic HIV-1 carriers. We propose to extend this previous research by studying neurocognitive functioning in subjects at more advanced disease stages who are likely to evidence more frequent and pronounced cerebral changes associated with HIV and related pathogens. We will thus follow a subset of the original HNRC cohort as well as recruit a new, ethnically diverse sample that is at a relatively advanced disease stage at study entry. The NP assessment will consist of a more efficient, but still comprehensive, test battery. Subjects will receive annual NP evaluations, with those at increased risk of death (T4<100) being seen every six-months. A multidisciplinary team will determine the clinical diagnosis for each subject (e.g., Minor Cognitive Motor Disorder [MCMD] and HIV-associated Dementia [HAD]). The identification of likely predictors (host and viral factors involved in susceptibility and pathogenesis) and outcomes (progressive neurobehavioral deterioration and early death) of NP impairment, particularly in subjects receiving a diagnosis of MCMD, will be emphasized. It is predicted that NP impairment will be significantly related to the presence of biological markers in the CSF, and NP functioning will decline as these levels increase. In particular, increases in HIV-1 viral burden, viral strains exhibiting enhanced replication in macrophage-endothelial cell cultures, and CMV virus load are expected to be associated with neurocognitive impairment. We will also examine the sensitivity and specificity of less invasive indicators of possible CMV infection in the brain, notably the presence of CMV retinitis and HLA types associated with increased susceptibility to CMV disease. By evaluating risk factors and outcomes associated with specific diagnoses (e.g., MCMD, HAD), we will be able to better assess the origins and prognostic value of these clinical syndromes. The relationship between the neuronal damage and behavioral manifestations commonly seen in HIV infection is poorly understood, despite the fact that neuropathologic changes are frequently noted at autopsy. We will thus correlate pre-agonal NP functioning and postmortem regional measurements of viral burden (gp41) and dendritic damage (using recently developed processes). The role CMV plays in neurocognitive impairment will also be better clarified by neuropathological determination of the presence of HIV encephalitis and CMV encephalitis.